During the past century, antibodies have been used therapeutically. Initially, therapeutic antibodies were administered as the naturally occurring polyclonal mixture from sera from immunized animals. While these products were efficacious, the serious side effects created by the anti-animal immune response of patients limited their use. Subsequently, monoclonal antibodies recovered from immunized mice were spliced onto a human constant region to produce chimeric antibodies that are approximately 70% human and 30% murine. The intensity of the anti-murine antibody response in patients treated with chimeric antibodies is significantly reduced. The ultimate goal of recovering fully human antibodies from immunized animals has been achieved by inactivating the endogenous immunoglobulin genes and substituting their human counterparts in the animal genome.